DE4411025A1 - New lipopeptide A1437 derivs. with modified acyl gp. - Google Patents

Abstract

Lipopeptide A1437 derivs. of formula (I) and their salts are new: R1 = OH or NH2; R2 = 8-22C satd. or unsatd. aliphatic acyl, opt. interrupted by O, phenylene or cycloalkylene; R3 = H.

Description

The invention relates to derivatives of antibiotics of the lipopeptide complex A 1437, a process for their preparation and their use as pharmaceuticals.

In German Patent Application 43 19 007.3 lipopeptides are very homologous amino acid sequences, but different fatty acid residues (Lipidanteil) proposed by Actinoplanes sp. during the fermentation be synthesized and delivered into the culture medium and a method for the isolation of the lipopeptides from the culture medium and their purification, the Use of the lipopeptides as pharmacological agents, in particular against gram-positive bacteria.

The object of this invention is, then, for derivatives of the lipopeptide complex A 1437 with a lower toxicity compared to the natural A 1437 To look for lipopeptides.

This object is achieved by derivatives according to a Compound of the formula I.

The invention thus relates to:

• 1. Lipopeptide A 1437 derivatives of the formula I. wherein
  R¹ is OH or NH₂,
  R² is a straight-chain or branched saturated or unsaturated C₈-C₂₂ aliphatic acyl radical which may be interrupted by phenyl or cycloalkyl groups or by oxygen, and in which n is an integer between 0 and 20
  and their pharmaceutically acceptable salts.
• 2. A process for the preparation of a compound of the formula I, which comprises reacting a compound of the formula II wherein
  R¹ has the abovementioned meaning and
  R³ represents an amino protecting group known from peptide chemistry, preferably tert-butoxycarbonyl (BOC-), benzyloxycarbonyl- (Z-, Cbz-), fluorenylmethoxycarbonyl (Fmoc-) or allyloxycarbonyl- (Alloc-) protecting group,
  with a carboxylic acid of formula III, R²OH IIIworin
  R² has the meanings mentioned in claim 1
  or reacted with a derivatized on the carbonyl derivative of this carboxylic acid.
• 3. Medicaments containing a lipopeptide derivative according to formula I as well as pharmaceutical carriers.
• 4. Use of a lipopeptide derivative according to formula I for the preparation a drug for bacterial infections.

In the following the invention is described in detail, in particular in their preferred embodiments. Furthermore, the invention is characterized by the content of Claims determined.

The starting compounds (compounds of formula II) are known from the obtained protected fermentation products, eg. From A 1437 β (I, R¹ = OH, R² = (CH₃) ₂CH (CH₂) ₇CH = CHCH₂CO) and chloroformic acid (9-fluoro methyl ester to form the corresponding compound with

and subsequent enzymatic cleavage of the fatty acid residue by means of Actinoplanes utahensis NRRL 12052 (J. Antibiotics 1988, 1093).  

If the carboxylic acids of the formula III themselves are used as acylating agents, so it is useful in the presence of a condensing agent, for. B. one Carbodiimids such as N, N'-dicyclohexylcarbodiimide worked. Activation of the Carboxylic acids of the formula II can according to those customary in peptide chemistry Methods such as B. in "Chemistry in Our Time" 27, 274-286 (1993) are described done. Accordingly, activated derivatives are suitable Acid halides, e.g. Acid chlorides, anhydrides or mixed anhydrides, z. With formic esters, azides, activated esters such as p-nitrophenyl, Pentafluorophenyl, 4,6-dimethoxy-1,3,5-triazin-2-yl ester or ester with N-hydroxysuccinimide or 1-hydroxybenzotriazole with carbodiimides as Coupling reagents are obtained, or thioesters, z. B. with 2-mercaptobenzothiazole. Other suitable coupling reagents are N, N-carbonyldiimidazole or those based on phosphonium or Uronium salts such. BOP, HBTU, PyBOP, TBTU or TOTU (O- [cyano (ethoxycarbonyl) methylidene) amino-1,1,3,3-tetramethyl] uronium tetrafluoroborate).

In general, the reaction of the compounds of formula II is carried out with a Carboxylic acid of the formula III or its activated derivative in the presence of a inert solvent such. For example dichloromethane or dimethylformamide, preferably in the presence of a tertiary base such as. As pyridine or Ethyldiisopropylamine. When using substituted benzoyl chlorides can also in the presence of water and addition of bases such as pyridine or Sodium carbonate are worked. The implementation can be done in one Temperature range from 200 to + 500, preferably between -10 ° and + 30 ° C.

The cleavage of the protective groups R³ to form the compounds I takes place by literature methods, for. B. is the BOC group with Trifluoroacetic acid, the Z-residue with HBr / glacial acetic acid or by catalytic Hydrogenation, the Alloc group with nucleophile plus Pd catalyst or the Fmoc Group with secondary amines, e.g. As piperidine cleaved.  

Preference is given to the compounds of the formula I in which
R² is a saturated aliphatic acyl radical CH₃ (CH₂) _n CO,
a branched saturated aliphatic acyl radical, preferably (CH₃) ₂CH (CH₂) _n CO or CH₃CH₂CH (CH₃) (CH₂) _n CO,
an unsaturated aliphatic acyl radical which may contain one or more double bonds, wherein a double bond may be in the trans or cis form, preferably H₂C = CH (CH₂) _n CO, (CH₃) ₂CH (CH₂) _n CH = CH (CH₂ ) _n CO,
CH₃ (CH₂CH = CH) _n (CH₂) _n CO, CH₃ (CH₂) _n CH = CH (CH₂) _n CH = CH (CH₂) _n CO,
CH₃ (CH₂) _n CH-CH-CO, CH₃ (CH₂) _n CH = CH (CH₂) _n CO, H (CH₂, -C (CH₃) = CHCH₂) _n CO,
an unsaturated aliphatic radical having one or more triple bonds, preferably HC≡C (CH₂) _n CO, CH₃ (CH₂) _n C≡C (CH₂) _n CO,
CH₃ (CH₂) _n C≡C≡C (CH₂) _n CO,
an aliphatic acyl radical interrupted by phenyl or cycloalkyl radicals, preferably

an acyl radical interrupted by an oxygen, preferably

and where n is integers between 0 and 20.

Particularly preferred are the compounds which have a straight-chain or branched C₁₂-C₁₅ acyl radical, such as. B. tetradecanoyl, tridecanoyl, 12-Methyltridecanoyl, an unsaturated C₁₂-C₁₈ acyl radical with one or multiple double or triple bonds, such. Cis 10-pentadecenoyl, trans-9-hexadecenoyl, H (CH₂-C (CH₃) = CHCH₂) ₃CO or a by 1-3  Phenyl radicals and / or additionally interrupted by oxygen aliphatic Acyl radical, such as. B.

where n is an integer between 0 and 8.

Very particularly preferred are the compounds which have a by 3 Phenyl groups interrupted aliphatic acyl radical, such as. B.

wherein n integers between 0 and 2 mean.

The invention further includes a process for the preparation of compounds of the formula I, which is characterized in that a compound of formula II

wherein
R¹ has the abovementioned meaning and
R³ is an amino protecting group known from peptide chemistry, e.g. The tert-butoxycarbonyl (BOC-), the benzyloxycarbonyl- (Z-, Cbz-), the fluorenylmethoxycarbonyl (Fmoc-) or the allyloxycarbonyl- (Alloc-) protecting group,
with a carboxylic acid of the formula III,

R²OH III

wherein R² has the meanings already mentioned,
implements.

As pharmaceutically acceptable salts of the compounds of formula I are salts with inorganic and organic acids, eg. Hydrochloric acid, sulfuric acid, Acetic acid, citric acid, p-toluenesulfonic acid, with inorganic and organic bases such as NaOH, KOH, Mg (OH) ₂, diethanolamine, ethylenediamine or with amino acids such as arginine, lysine, glutamic acid, etc. especially useful. They are manufactured according to standard regulations.

A one or more compounds of the lipopeptides or their salts are suitable because of their valuable pharmacological properties for use as a medicinal product.

The substances according to the invention have pharmacological activity especially as an antibiotic against gram-positive bacteria, especially preferred against MRSA and glycopeptide resistant strains.

In penicillin or methicillin-resistant strains (MRSA strains), the have trained more resistance to antibiotics, often possess only Glycopeptides such as vancomycin or teicoplanin a therapeutically sufficient  Effect. Increasingly, however, are also resistant to these antibiotics Strains (FEMS Microbiol. Lett. 98 (1992) 109 to 116). One or more Compounds of the lipopeptides according to the invention have an excellent Effect against these problem germs.

The application also relates to pharmaceutical preparations one or more Compounds of the lipopeptides or their salts according to the invention.

One or more compounds of the lipopeptides of the invention are preferred one or more compounds with 3-phenyl radicals in the acyl radical R can basically be administered as such in substance. Preferably, the Use in mixture with suitable excipients, carrier material or Diluents. As a carrier material for veterinary drugs, the usual feed mixtures or in humans all pharmacologically compatible carrier materials and / or auxiliaries.

The pharmaceutical compositions according to the invention are generally oral or parenteral administered, but also a rectal application is possible in principle. suitable solid or liquid galenic preparations are, for example Granules, powders, tablets, dragees, (micro-) capsules, suppositories, syrups, Emulsions, suspensions, aerosols, drops or injectable solutions in Ampoule form and preparations with protracted drug release in which Manufacture usually carriers and additives and / or aids such Explosive, binding, coating, swelling, lubricating or lubricating agents, Flavorings, sweeteners or solubilizers find use. As commonly used carriers or excipients z. For example, magnesium carbonate, Titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, Starch, Vitamins, Cellulose and their Derivatives, Animal Vegetable Oils, Polyethylene glycols and solvents, such as sterile water, alcohols, Called glycerine and polyhydric alcohols.  

As diluents may be mentioned, for example, polyglycols, ethanol and Water. Buffer substances are, for example, organic compounds, such as z. N ', N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, Tris (hydroxymethyl) aminomethane, or inorganic compounds, such as. B. Phosphate buffer, sodium bicarbonate, sodium carbonate. It is also possible that Active substances as such without carrier or diluent in a suitable form to apply. Suitable doses of the compounds of the formula I or their pharmaceutically acceptable salts are about 0.4 g, preferably 0.5 g up to a maximum of 20 g per day for an adult of about 75 kg Body weight. There may be single or generally multiple doses be administered, wherein the single dose of the active ingredient in an amount of may contain about 50 to 1000 mg.

Optionally, the dosage units for oral administration be microencapsulated to delay the delivery or over a longer period Period, such as by coating or embedding the Particle active ingredient in suitable polymers, waxes or the like.

Preferably, the pharmaceutical preparations are in dosage units prepared and administered, each unit as an active ingredient certain dose one or more compounds of the invention Contains lipopeptides. For solid dosage units such as tablets, capsules and Suppositories may dose up to about 200 mg, but preferably about 0.1 up to 100 mg, and in the case of injectable solutions in ampoules up to approximately 200 mg, but preferably about 0.5 to 100 mg, per day.

The daily dose to be administered depends on the body weight, age, Sex and condition of the mammal. In some circumstances, however, too be higher or lower daily doses. The administration of the Daily dose can be given by single dose in the form of a single  Dosage unit or in several smaller dosage units as well by multiple subdivided doses at specific intervals.

The medicaments according to the invention are prepared by reacting or several compounds of the lipopeptides of the invention with conventional Carrier and optionally additives and / or adjuvants into or a brings appropriate dosage form.

The particularly preferred compounds of the formula I with 3 phenyl radicals in the Moreover, acyl radical R 2 (eg 55, 56) has particularly favorable properties toxicological properties. So they show in the standard hemolysis test practically no evidence of hemolysis during all tested compounds with straight-chain or branched aliphatic acyl radicals including Natural products have a considerable activity between 16 and 25% (Table 1).

Hemolytic activity in vitro²) example Hemolysis (%) A 1437¹) XCF₃CO₂H 17.5 1 19.6 6 16.5 7 25.7 8th 19.3 9 22.8 14 22.9 49 0.0 55 0.5 56 0.4

¹) fermentation product I (R¹ = OH, R² = (CH₃) ₂CH (CH₂) ₇CH = CHCH₂CO)
²) To measure hemolytic activity, freshly drawn venous blood from rhesus monkeys is used. The blood is collected in heparinized tubes and distributed in aliquots of 200 ml to 12 polyethylene tubes. One aliquot is added with 200 ml of distilled water and used as 100% standard, another is mixed with 200 ml of physiological saline (0.9% NaCl) (0% standard). 200 ml of dilutions of the substance in saline at 1600, 800, 400, 200, 100, 50, 25, 12.5, 6.25 and 3.125 mg / l are distributed to the remaining tubes. All tubes are gently swirled and then incubated for 3 hours at 37 ° C. The 100% standard is then filled with 5 ml of distilled water, the rest with 5 ml of physiological saline and centrifuged for 5 minutes at 700 g.

The hemolysis is done by measuring the absorption of the supernatant in one Spectrophotometer determined at a wavelength of 540 nm. The Absorption of the standard with complete hemolysis (aqua dest.) Is considered 100% set. The absorptions of the test preparation dilutions and the 0% Standards are measured and percent maximum inducible hemolysis specified.

The following exemplary embodiments can be produced according to the invention Compounds serve to further explain the invention.

In the following examples, the invention will be further explained. Percentages are by weight. Mixing ratios Liquids are by volume unless otherwise stated were made.

The purity of the reaction products is determined by analytical HPLC (Merck, Darmstadt, LiChrospher® 100RP-8, 125 × 4 mm, elution system water + Trifluoroacetic acid pH 2.5, 0.1% sodium octanesulfonate / acetonitrile, detection  with UV at 220 nm) determines the structure by means of electrospray Mass spectroscopy BIO-Q-MS).

For convenience, the term A 1437 cyclopeptide for the Compound I with R² = hydrogen needed.

example 1 Tridecanoyl derivative of A 1437 cyclopeptide Compound I, R¹ = HO, R² = CH₃ (CH₂) ₁₁CO) TOTU coupling procedures a) Activation of tridecanoic acid

113 mg (0.527 mmol) of tridecanoic acid are dissolved in 3.75 ml N, N'-dimethylformamide (DMF) dissolved, 172.5 mg (0.526 mmol) TOTU and 1.25 g of a solution of ethyldiisopropylamine (0.5 mmol) in DMF (0.4 mmol / g) was added. The solution is left at room temperature for 1 hour leave.

b) coupling

348 mg (0.264 mmol) of Fmoc derivative II (R¹ = OH, R³ = fluorenylmethoxycarbonyl; Example 69) are dissolved in 7.2 ml of dry DMF and 2.9 g of the active solution a) (0.25 mmol) in an ice bath added. The brownish solution formed is 1.5 hours at Room temperature stirred.

c) Cleavage of the Fmoc protecting group

The solution b) is cooled to 100, 6 ml of piperidine was added and Stirred for 1 hour at room temperature. Then it is with 250 ml of water diluted and freeze-dried.  

d) cleaning

The freeze-dried residue is suspended in 100 ml of water / acetonitrile (5: 1), adjusted to pH 2.0 with 1.5 ml of 2NHCl and the clear solution over 90 g of RP₁₈ silica gel (Merck, Art. 9303) with water + 0.01% CF₃COOH / acetonitrile Chromatograph. Elution sequence: 500 ml 3: 1, 500 ml 2: 1, 600 ml 1: 1 mixture. The title compound appears in the 1: 1 fraction (UV detection 220 nm).
Yield 267 mg (78% of theory)
Purity 72%.

The crude product is rechromatographed on a Buchi medium-pressure column (250 g RP₁₈, elution with water + 0.01% CF₃COOH / acetonitrile (3: 2)). The product fractions are freeze-dried.
Yield: 130 mg, purity: 96%
C₅₈H₉₃N₁₃O₂₀ [1292.5] MS: 1293

Example 2 4-Octylbenzoyl derivative of A 1437 cycloeptide Acid chloride method a) coupling

6.6 mg (0.005 mmol) of Fmoc derivative II (Example 69) are dissolved in 200 mg Pyridine / water (9: 1) and dissolved at -20 ° C 25 mg (0.1 mmol) 4-Octylbenzoyl chloride added. The solution is added for 4 hours Room temperature stirred. After adding 2 ml of dioxane, the Solvent in vacuo and the residue in 0.2 ml of DMF solved.  

b) Cleavage of the Fmoc protecting group

To the solution a) 0.2 ml of piperidine are added and at 1 hour Leave room temperature. The solution is diluted with 5 ml of water and freeze-dried.

c) cleaning

The freeze-dried residue is chromatographed over 10 g of RP₁₈ silica gel with water + 0.01% CF₃COOH / acetonitrile. Elution sequence: 80 ml 3: 1, 80 ml 2: 1, 80 ml 1: 1 mixture. The 1: 1 product fraction is freeze-dried.
Yield: 4.6 mg (70% of theory), purity: 85%
C₆₀H₈₉N₁₃O₂₀ [1312.5] MS: 1313.

Analogously to Example 1, the compounds listed below are the Formula I wherein R¹ = HO and the in Table 2 bear specified substituents R. The yields are between 60 and 85% of theory, the purity between 75 and 98%.  

Table 2

Analogously to Example 2, the compounds listed below are the Formula I wherein R¹ = HO and the in Table 3 bear specified substituents. The yields are between 70 and 85% of theory, the purity between 80 and 98%.  

Table 3

Analogously to Example 1 (compounds 59-66) or Example 2 (compounds 67 and 68), the compounds of the formula I listed below are obtained, wherein R¹ = NH₂ and the substituents indicated in Table 4 Wear R². The yields are between 75 and 85% of theory the purity between 80 and 98%.

Table 4

Preparation of the starting compounds Example 69 9-Fluorenylmethyloxycarbonyl derivative of A 1437

10 g (7.67 mmol) of A 1437 (I, R¹ = HO, R² = (CH₃) ₂CH (CH₂) ₇CH = CHCH₂CO) and 3.24 g (38.35 mmol) of sodium bicarbonate are dissolved in a mixture of 920 ml of water and 640 ml of acetone. Under pH control, a solution of 2.97 g (11.5 mmol) of chloroformic acid (9-fluorenylmethyl) ester in 240 ml of acetone is then added dropwise at pH 8.5 over the course of 100 minutes. In this case, the reaction solution is heated to 27 ° C. It is stirred for 1 hour at room temperature. After removal of the acetone in vacuo, the aqueous solution is freeze-dried. The colorless residue is stirred twice to remove low molecular weight impurities with 500 ml of methylene dichloride.
Yield: 12.2 g, MS: 1526.7

Example 70 9-fluorenylmethyloxycarbonyl derivative of A 1437 cyclopeptide

A mixture of 10 g of product from Example 69 and 300 g of moist mycelium Actinoplanes utahensis in 1 l of sterile potassium phosphate buffer (100 mmol, pH 7.2, 50 mmol EDTA, 0.02% sodium azide) is stirred for 48 hours at 32 ° C.  

The biomass is then separated by centrifugation, the solution is filtered to fix the product over 500 g of MCI gel (Mitsubishi) and the product with water / methanol (1: 1) eluted. The eluate is concentrated to remove methanol and the aqueous solution over 500 g RP₁₈ with water + 0.05% trifluoroacetic acid / acetonitrile (2: 1) chromatographed. The product fractions are concentrated in vacuo and freeze-dried.
Yield: 6 g, MS: 1318.4

Example 71 4 - ((2- (4- (2-phenylethyl)) phenylethyl)) benzoic acid

A solution of 22.9 g of methyl 4-bromomethylbenzoate in 1000 ml of toluene is mixed with 33.9 g of triphyenylphosphine and heated under reflux. After 7 hours, the conversion is complete. It is allowed to cool and the product is filtered off with suction.
Yield: 47.6 g

Level 2

58.9 g of stage 1 are suspended in 500 ml of anhydrous tetrahydrofuran, cooled to 0 ° C and treated with 120 ml of a 1 M solution of lithium bis-tri methylsilylamid in tetrahydrofuran. After 1 hour at room temperature, the mixture is cooled again to 0 ° C. and 19.3 g of stilbene-4-aldehyde are added. Then it is stirred for 2.5 hours at 50 ° C, cooled to 0 ° C and the precipitated solid is filtered off with suction. The residue is washed with 0.5 l of THF. The organic phase is diluted with 750 ml of ethyl acetate and washed with 750 ml of sat. Washed ammonium chloride solution. The water phase is extracted with 750 ml of ethyl acetate, the organic phase dried over sodium sulfate and concentrated. The crude product is used in the next step.
Yield: 49.9

level 3

26.7 g of crude product from stage 2 is suspended together with 5 g of palladium on activated carbon (10% Pd) in 1000 ml of methanol. It is hydrogenated for 3 hours at room temperature under atmospheric pressure. The catalyst is filtered hot, the solution concentrated in vacuo and the product purified by chromatography on silica gel with heptane ethyl acetate (10: 1).
Yield: 7.4 g

Level 4

1.98 g of stage 3 are suspended in 60 ml of ethanol and treated with a solution of 508 mg KOH in 10 ml of water. The solution is refluxed for 1.5 hours. The ethanol is removed in vacuo, the residue is taken up in 500 ml of ethyl acetate and 200 ml of water and the solution is adjusted to pH 2 with 2NHCl. The mixture is stirred for 0.5 hours, the phases are separated and the aqueous phases are extracted once more with 200 ml of ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo.
Yield: 1.86 g of the title compound

acid chloride

1.23 g of stage 4 are suspended in 10 ml of thionyl chloride. Then it is heated under reflux until the evolution of gas has ended. After cooling, it is concentrated in vacuo and evaporated twice with 5 ml of toluene.
Yield: 1.35 g light gray crystalline compound

Example 72 4- (2- (biphenyl-4-yl) ethyl) benzoic acid step 1

Analogously to stage 2 in example 71, 6.4 g of phosphonium bromide (stage 1 from example 71) are reacted with 1.82 g of biphenyl-4-aldehyde.
Yield: 5.8 g

Level 2

5.8 g of stage 1 are hydrogenated analogously to stage 3 in example 71 and the product is purified by chromatography.
Yield: 970 mg

level 3

950 mg of Step 2 are saponified analogously to Step 4 in Example 71.
Yield: 880 mg

Level 4

850 mg of stage 3 are reacted with thionyl chloride analogously to stage 5 in example 71 to the acid chloride.
Yield: 909 mg.

Claims (8)

1. Lipopeptide A 1437 derivatives of the formula I. wherein
R¹ is OH or NH₂,
R² is a straight or branched saturated or unsaturated aliphatic C₈-C₂₂-acyl radical which may be interrupted by phenyl or cycloalkyl groups or by oxygen
and their pharmaceutically acceptable salts. 2. lipopeptide derivative according to claim 1, characterized in that R²
a saturated aliphatic acyl radical CH₃ (CH₂) _n CO,
a branched saturated aliphatic acyl radical, preferably (CH₃) ₂CH (CH₂) _n CO or CH₃CH₂CH (CH₃) (CH₂) _n CO,
an unsaturated aliphatic acyl radical which may contain one or more double bonds, wherein a double bond may be in the trans or cis form, preferably H₂C = CH (CH₂) _n CO, (CH₃) ₂CH (CH₂) _n CH = CH (CH₂ ) _n CO,
CH₃ (CH₂CH = CH) _n (CH₂) _n CO, CH₃ (CH₂) _n CH = CH (CH₂) _n CH = CH (CH₂) _n CO,
CH₃ (CH₂) _n CH-CH-CO, CH₃ (CH₂) _n CH = CH (CH₂) _n CO,
H (CH₂, -C (CH₃) = CHCH₂) _n CO
an unsaturated aliphatic radical having one or more triple bonds, preferably HC≡C (CH₂) _n CO, CH₃ (CH₂) _n C≡C (CH₂) _n CO,
CH₃ (CH₂) _n C≡C≡C (CH₂) _n CO,
an aliphatic acyl radical interrupted by phenyl or cycloalkyl radicals, preferably an acyl radical interrupted by an oxygen, preferably and where n is integers between 0 and 20. 3. lipopeptide derivative according to claim 1, characterized in that
R¹ is OH or NH₂
R² is a straight-chain or branched C₁₂-C₁₅ acyl radical, preferably tetradecanoyl, tridecanoyl, 12-methyltridecanoyl, an unsaturated C₁₂-C₁₈ acyl radical having one or more double or triple bonds, preferably cis -pentadecenoyl, trans-9-hexadecenoyl, H (CH₂- C (CH₃) = CHCH₂) ₃CO or an aliphatic acyl radical interrupted by 1-3 phenyl radicals and / or additionally by oxygen, preferably and where n is an integer between 0 and 8. 4. lipopeptide derivative according to claim 1, characterized in that
R¹ is OH or NH₂
R² is an aliphatic interrupted by 3 phenyl groups
Acyl radical, preferably where n is an integer between 0 and 2. 5. A process for the preparation of a compound of the formula I, which comprises reacting a compound of the formula II wherein
R¹ has the abovementioned meaning and
R³ is an amino protecting group known from peptide chemistry, preferably tert-butoxycarbonyl (BOC-), benzyloxycarbonyl- (Z-, Cbz-), fluorenylmethoxycarbonyl (Fmoc-) or allyloxycarbonyl- (Alloc-) protecting group,
with a carboxylic acid of the formula III, R²OH IIIworin R² has the meanings given in claim 1,
or reacted with a derivatized on the carbonyl derivative of this carboxylic acid. 6. Lipopeptide derivative according to formula I for use as a medicament. 7. Medicaments containing lipopeptide derivative according to formula I and pharmaceutical carriers. 8. Use of a lipopeptide derivative according to formula I for the preparation a drug for bacterial infections.